Handout for the NAS (Surrey Branch) Conference

University of Surrey, Guildford, 8th June 2002


Paul Shattock; Paul Whiteley, University of Sunderland. England.


The Development of a Logical System for the Implementation of Biomedical Therapies in Autism Spectrum Disorders


The notion that food derived peptides with opioid activity are involved in the causation of autism spectrum disorders arose from two main areas.


Panksepp, in 1979, noted the similarities between the symptoms of autism and those seen in people who had used morphine like substances for a considerable period of time. Morphine acts by mimicking the activity of substances which occur naturally in the brain. These substances are peptides known generically as “endorphins”. These peptides consist of short chains of amino-acids and it is likely that morphine and its derivatives produce their opioid activity because they are the same shape as these peptides. They fit the receptors precisely and stimulate them in the same way as the naturally occurring peptides.


Many parents had observed that certain foods exacerbated the symptoms of autism and, as a result, had eliminated them from the diet of their children. They claimed that this ameliorated their problems. The two foods most consistently reported were the proteins gluten (from wheat and other cereals) and casein (derived from bovine and other milks). Proteins are made up of very long chains of amino-acids which are arranged like beads on a string. During the process of digestion, the large proteins are broken down into smaller peptides before being further broken down into the amino-acid components. Some of these peptides obtained from gluten and casein are very similar to those endorphins found in the brain. These are known as casomorphins and glutemorphins and the structures are now well established.


It was hypothesised that these peptides could, under certain circumstances, be absorbed from the intestines into the blood stream. If that occurs, the majority would be deposited in the urine where we and other workers throughout the world have been finding and identifying them for some years now. The brain is protected from such compounds circulating in the blood by a “blood-brain-barrier” (BBB). However, this is not totally impervious and a proportion of these peptides will cross into the brain. They may either have direct opioid effects there or could form a substrate for the enzymes which would, under normal circumstances, break down the endorphins once they had done their job. Either way, the effects would be the same. There would be increased opioid activity.


These opioid peptides act as neuro-regulators or modulators. They can affect the function of all the main types of neurones in the brain and cut down (or enhance) transmission in all the systems. The consequences will include perceptual and cognitive problems; changes in behaviour, in mood and emotional response. Opioid peptides are also implicated in the functioning of the immune system and, at certain times, in brain development and maturation.


When children are about two years of age, they have many more neurones than they actually require throughout life. Those that are not required are “pruned”. This is a part of natural development for many systems which would have been of use to mankind in past millennia but are no longer beneficial. The systems which are not employed are destroyed. The main agents involved in this pruning are the opioid peptides. If the levels are too high at this critical time, the pruning that occurs will be abnormal. It could be over or under zealous depending upon the peptide concentrations available. The abnormalities of structure reported by Bauman and Courchesne are entirely consistent with this concept. The importance of early intervention, which can only follow early diagnosis, is obviously immensely important.


However, the brain is much more plastic than had previously been believed. Although there is little evidence to suggest regeneration of actual cells occurs, it is clear that the brain is a dynamic entity and that new connections and circuits do form when the insulting peptides are removed from the system. Removal of these peptides could also encourage more normal neurotransmission to occur.


Any use of dietary intervention must, like all other interventions, be seen as a part of an overall treatment plan. There is absolutely no point in taking the breaks off the car (removing the peptides) unless there is fuel in the tank (in terms of intensive education and therapy). The best results are seen in those children where therapy combines these two elements.


Structures of the Peptides


Some of these peptides have now been isolated from the urine and identified precisely. Bovine casomorphins and glutemorphins have been shown to be present using a number of techniques (HPLC; immuno-assays; Mass Spectrometry etc). These are not human products and, given the quantities involved, can only have been derived from ingested food.


There are also a number of other closely related compounds which have been isolated. Reichelt has identified some novel compounds which act as selective serotonin uptake stimulators; Friedman has identified powerful opioid substances which could be derived from intestinal bacteria. During our investigation of these compounds we located a marker compound which was present in elevated levels in some 80% of people with autism (in the UK) and associated disorders. This compound, Indolyl Acryloyl Glycine (IAG) is present in the urine of each of us but people with autism excrete considerably higher levels.


It should be noted that the presence of this compound in high levels, although characteristic of autism spectrum disorders (ASD), is not absolutely diagnostic. It appears in similar levels in about 20-25% of asymptomatic controls and in about 50% of first degree family members (UK figures). This would appear to confirm some genetic significance. It is well known that there are increased incidences of associated disorders (ADD; ADHD; Speech and Language problems) in our families and, perhaps, a predisposition to select certain careers (Engineering; Architecture; Computer Technology etc) and it may be that some of the milder characteristics associated with autism would be beneficial in these occupations!


Our theoretical model may be illustrated visually in Figure 1.


Figure 1           

In Figure 1, the stars represent peptides.  Figure 1A represents the normal situation. We all produce low levels of peptides when we digest proteins. Small quantities will pass from the intestines into the bloodstream and thence on to the Central Nervous System (CNS). Figure 1B represents the situation where there are excessive levels of peptides in the urine. This could be for a variety of reasons but the result will be the passage of elevated levels of peptides to the CNS. There may be, (as in Figure 1C) excessive permeability of the intestines which will encourage passage of peptides. Some of the reasons for this are given below but this could also result from a lingering infection in the intestinal wall. It is suggested that this permeability could be the result of a sub-acute intestinal measles infection resulting from a vaccination programme that includes multiple infections with attenuated strains of the diseases. In Figure 1D, there is excessive permeability of the Blood Brain Barrier. This could result from physical injury or infectious or other diseases.

The process by which intact peptides can pass from the intestines to the brain and affect development and activity may be complex but the notion is, in itself, comparatively simple.


IAG is an abnormal metabolite of the amino-acid “tryptophan”. The limited amount of available evidence suggests that IAG itself is comparatively innocuous (although this may not prove to be the case). As tryptophan is being converted into IAG, it is converted to Indole Acrylic Acid (IAcrA) and it is this compound which may have the more serious consequences. It is a planar and very reactive molecule and could have a variety of effects in the body. We speculate that it becomes involved in the lipids that make up cell membranes. It could, by replacing fatty acids, become directly incorporated into the fats themselves but this is not certain. Alternatively (or additionally) it could become deposited between the lipid layers that make up membranes. These would, under these conditions, greatly reduce the flexibility of these membranes (including those surrounding red blood corpuscles). If these effects do occur (and work is proceeding to test these hypotheses) the consequence would be greatly increased permeability of the intestinal wall and of the blood brain barrier. In the presence of this compound, the passage of peptides from the intestines to the brain would be greatly facilitated.


There may be other reasons for increased permeability of these membranes. Deficiencies in sulphation processes would cause this and so would severe infections with yeasts or some other intestinal parasites. Physical damage to the intestines could be involved. Alternatively, infections of the intestinal wall could result in this increased permeability.


Inside the intestines themselves, we should look for deficiencies in the process by which proteins are broken down into amino-acids. We must seek reasons for the process becoming arrested at the peptide stage. This could result from:-


a) the presence of levels of gluten and casein which are beyond the capabilities of the digestive process in the individual; (remove from diet).

b) a shortage of the natural peptidase enzymes (supplementation directly with “bromelain” , “Seren-Aid” or “Enzyme-Aid”  or encouraging the pancreas to produce appropriate levels with secretin).

c) insufficient acid in the stomach (betaine hydrochloride supplementation);

d) insufficient co-factors (supplement vitamins and minerals);

e) presence of intestinal parasites such as yeasts, Giardia or worms (eradicate).


There are factors which may increase the permeability of the intestinal wall and which will lead us to a number of interventions which could be used to ameliorate this problem.


a) incomplete sulphation (sulphate, in the form of Epsom Salts (Magnesium Sulphate) in bathwater or patches; MSM) (removal of phenolic or salicylate containing foods).

b) inappropriate acids in the membrane lipids (evening primrose oil followed by other oils (such as fish and flax oils)

c) insufficient nutrients for intestinal wall (glutamine)


There is little that can be done to increase the integrity of the blood brain barrier but the advisability of utilising combination vaccines where there are reasons to suspect immune systems which are compromised by immaturity or other infections must be questioned.


The Sunderland Protocol


The Autism Research Unit’s main objectives are to investigate the biological mechanisms, which may underlie autism, and the implications these may have for the development of therapeutic regimes. In the course of this work we have obtained clinical information, including urinary peptide analyses on over 7,500 subjects with ASDs and other related disorders such as Chronic Fatigue Syndrome; Gulf War Syndrome; Obsessive Compulsive Disorder; Dyspraxia and others. More often than not, as a result of our investigations, we are requested to advise parents and carers on appropriate interventions. We would question the ability or the right of anyone, medically qualified or not, to make recommendations for subjects they have not seen and that they know only through a series of clinical notes and chemical tests.


We have developed a protocol, "The Sunderland Protocol", which consists of a sequence of interventions that we feel to be logical and which can be used with a minimal possibility for adverse reaction. The protocol is divided into three sections and is based loosely upon the Northern Ireland Peace Process.


We strongly advise the active involvement of an experienced dietitian (UK) or nutritionist (US) and the support of a medical practitioner when implementing these interventions. We would also prefer to see allergy testing for possible Celiac Disease performed before embarking on this process.


We are of the opinion that even without biological testing, there is sufficient evidence to support the use of these interventions sequentially. There can be no guarantees that any particular intervention will benefit any one particular child. We have been proven wrong so many times in our predictions of efficacy or otherwise that we regularly introduce the following system for consideration.


There will be those who opt for a different sequencing (DMG or Yeast removal first for example). We suggest that people revisit a failed intervention from time to time and that they test the effectiveness of the interventions they are using as we have found, repeatedly, that the effectiveness of a particular intervention will alter with development and with the nature and extent of other programmes.




Stage 1 - The Cease-fire.


This involves removal of the guns and the bullets, in this case gluten and casein for an appropriate period.


 Stage 2 - The Preliminary (Good Friday) agreement.


Keeping a diary to look for other dietary insults; consideration of vitamin, mineral, and allergy irregularities; consideration of other intestinal parasites.


It is our experience that testing is best performed at this stage, after the removal of the smokescreen caused by the gluten and casein products. We have found that many of the myriad allergies detected before the exclusion of these products disappear at this stage whilst others become unmasked. Similarly, we have found that vitamin and mineral status irregularities may have dissipated as the intestinal function returns.


Stage 3 - The Active Reconstruction Process.


The ultimate intention must be to re-establish the efficiency of the processes of digestion and absorption. If this can be achieved, it is conceivable that dietary regimes could be much less severe. The sequence we propose can be found on the accompanying page.


This section includes a number of possibilities some of which (DMG and High doses of Vitamin B6 and Magnesium) have an excellent record. Also included are other therapies (secretin, for example) which certainly appear promising, as well as safe, but for which medical support is essential. The use of severely exclusive diets devoid of phenols (pigments) or salicylates are placed at this stage purely because they are more intensive and obtrusive into a normal lifestyle.


Stage 4 – Other Interventions.


We would never suggest that these interventions are the only possibilities. Many other interventions, which initially seemed ludicrous or without scientific validation are being utilised by parents who report benefits. Chelation; Organic Diets; Cranial Osteopathy and many other therapies may yield benefits.


Some Additional Notes


The use of any of these interventions must be seen as part of a total programme for each individual child. Such programmes should include educational, social and health inputs. These interventions are complementary not alternative.

Do not cease other prescribed medication without the authorisation and approval of the prescribing physician.

For further detailed information: visit our website at http://osiris.sunderland.ac.uk/autism   and check out the Sunderland Protocol.


This article is reproduced by kind permission of the author © Paul Shattock 8th June2002
© for the NAS Surrey Branch 2002.


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